Obesity has reached epidemic proportions in the United States and abroad. During the last decade it has become evident that excesses in inflammatory mediators such as TNF-?, IL-1? and IL-6 belie much of the pathogenesis associated with obesity. Complications associated with obesity include problems with tissue repair and barrier function. The mechanisms that cause impaired skin function in obesity are just beginning to be uncovered. Our lab and others have shown that populations of dendritic epidermal T cells reside in the epidermis where they regulate epithelial cell homeostasis and tissue repair. We have determined that chronic TNF-? production associated with obesity induces exhaustion and dysfunction of dendritic epidermal T cells. Here we propose to elucidate the mechanisms by which TNF-? regulates dendritic epidermal ?? T cell homeostasis and effector function. The proposed studies will begin to unravel the complex interplay between protective, healthy inflammation to improve wound healing and disease states with chronic TNF-? production that results in epidermal T cell exhaustion and dysfunction in wound repair. The following specific aims are proposed: Aim 1. Determine the role of TNF-? in costimulation of DETC to augment wound repair functions. Aim 2. Delineate the mechanism by which chronic TNF-? exposure in obesity causes DETC exhaustion. Aim 3. Identify how to restore DETC function in obesity and type 2 diabetes by regulating TNF-? responses. These specific aims will be tested in murine models of obesity combining cell biology, biochemistry and molecular biology techniques. Together these studies will carefully elucidate the basis for epidermal T cell regulation by TNF-?. We are in a unique position to test these aims due to our background in studying epidermal ?? T cell function and obesity. The projects described herein will provide hands-on research opportunities for undergraduate and graduate students at CSUSM. Participating in this research project will impact their ability to competitively apply for graduat level education or biotechnology positions. Together this experimental plan will culminate with the development of novel mechanisms of dendritic epidermal T cell regulation that can be evaluated to improve wound repair in obesity.